Inflammation is a complex biomolecular cascade of events stimulated by cellular damage, whether the damage is caused by physical trauma, toxins, pathogens, or burns. Inflammation is the body's protective response to removing or blocking off such injurious stimuli, and beginning the process of wound healing and tissue repair. However, inflammation is often accompanied by painful soreness, swelling, heat and redness, which may also lead to loss of function.
In many cases, prolonged inflammation, called chronic inflammation, causes ongoing tissue destruction and healing at sites of inflammation. This is true of the debilitating autoimmune disease, rheumatoid arthritis, in which synovial joints become stiff and painful as joint surfaces slowly erode, which may decrease range of movement and lead to loss of function.
But inflammation can also occur around joints in patients suffering from osteoarthritis. Osteoarthritis is a painful degenerative disease associated with age and decreased proteoglycan content around joints, thereby, making joints less resilient and more susceptible to degradation. Furthermore, painful bone spurs may also form along these damaged, swollen joints. Although osteoarthritis is not an autoimmune disease, it can also be caused by inflammatory diseases.
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce inflammation, along with their non-drowsy analgesic (pain relieving) and antipyretic (fever reducing) properties. Most NSAIDs serve as nonselective inhibitors of cyclooxygenase (COX), an enzyme that produces prostaglandins from arachidonic acid derived from the phospholipid bilayer of cellular membrane. Prostaglandins are the major signaling molecules involved in inflammation. Examples of NSAIDs include: acetaminophen, aspirin, ibuprofen, naproxen, and carprofen.
Carprofen is a selective cyclooxygenase-2 inhibitor that has been used in veterinarian medicine for decades to relieve postoperative pain, and to relieve chronic joint pain and inflammation associated with osteoarthritis, in dogs. Carprofen has the Chemical Abstracts Service (CAS) name of 6-Chloro-α-methyl-9H-carbazole-2-acetic acid and is a member of the carbazole family. Carbazoles have been synthesized as early as 1947, and their medicinal properties began to be studied shortly thereafter. Carprofen was first prepared in 1972 by Berger and Corraz of Hoffmann-La Roche Inc., as a useful anti-inflammatory and analgesic agent. Ulcer formation is a common side effect of many NSAIDs, especially if used often or in large dosages. Carprofen was believed to be advantageous over other NSAIDs because ulcer formation was rare. Hoffman La Roche began marketing carprofen as Imadyl in the early 1980s and this product was eventually sold to Pfizer for use in veterinary medicine as a chewable form, called Rimadyl, for dogs in the mid-1990s. However, non-chewable tablets of carprofen have been sold as a generic drug for many years.
The success of Pfizer's Rimadyl chewable tablet is likely attributed to better dog owner and dog compliance because of greater palatability over generic brands. Palatability is especially important for good dosing compliance in veterinary medicine with regards to owner administered oral tablets. Likewise, brands with reduced palatability can lead to poor owner and patient compliance, which often leads to missed doses or increased lag time between doses. Without good palatability, owners may try placing or crushing an oral tablet in food. Even so, the challenges faced by owners administering a non-palatable tablet to a reluctant animal can be frustrating when long-term dosing is required, such as for chronic illnesses, and can lead to noncompliance and poor clinical outcomes. So although different brands of a drug product, such as carprofen, are shown clinically to have equivalent safety and efficacy, i.e. bioequivalence, differences in palatability and compliance often remain.
The ideal oral tablet for veterinary medicine should be palatable and consumed voluntarily with an at least 90% voluntary acceptance rate. Palatability may be achieved by masking the foul taste of active pharmaceutical ingredients and/or by adding food based products or other flavors. Factors affecting palatability include taste, odor, appearance, and texture. However, the addition of flavoring agents generally change the dissolution profile of the drug and its bioequivalence. Yet, there remains a need to produce a more palatable and more voluntarily consumed orally administered tablet composition of carprofen that is easy to swallow, and has the same dissolution profile and bioequivalence of less palatable carprofen compositions, so that it can also be manufactured with greater ease and less cost than the available “chewable” tablet of carprofen (e.g., Rimadyl). As such, the preferred composition described herein is manufactured using the process of dry blending and tablet compression, and avoids the use of coatings; which require solvents, polymers and/or plasticizers, along with detackifiers, defoamers, surfactants; that can add much time and cost to the manufacturing process and can lead to problems of uniformity among tablets.